Legend:Exon: numbering of exons and intron/exon boundaries are according to ... with the
first base of the Met-codon counted as position 1 (see Reference
Sequence). Exon size: size of exon indicated in basepairs. Intron size:
size of intron indicated in kilobasepairs. 5' cDNA position: first base of the exon
(according to cDNA sequence reported by ...). Splice after: splicing occurs in
between of two coding triplets (0), after the first (1) or the second (2) base of a
triplet. Remarks: 5'UTR = 5' untranslated region, 3'UTR = 3' untranslated region.

The expression of A-type lamins is developmentally regulated. In
mouse, A-type lamins are absent from all pre-implantation stage
embryonic cells (including embryonal carcinoma cells). Expression appears at
about embryonic day 9 within the visceral endoderm and the
trophoblast (Stewart
& Burke 1987). Later, A-type lamins appear asynchronously in
various tissues. In certain cell types the proteins do not
appear until after birth (Rober et al. 1989).
A few cells, i.e. cells of the immune system, pancreatic islets and
Purkinje cells, only express B-type lamins (Rober et al.
1990).
These findings indicate that at the cellular level, A-type lamins are
nonessential.

The lamin A/C protein

Lamin A/C is an Intermediate Filament protein. IF proteins are primordial
components of the cytoskeleton and the nuclear envelope. They generally form
filamentous structures 8 to 14 nm wide. IF proteins are members of a very large
multigene family of proteins which has been subdivided in five major subgroups (see
SwissProt, PFAM00038);

Lamin A/C is a type V nuclear lamin. The lamins are components of the nuclear
lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane
which is suggested to provide a framework for the nuclear envelope and may
interact with chromatin.

All IF proteins are structurally similar and consist of;

a central rod domain comprising some 300 to 350 residues arranged in
coiled-coiled alpha-helices, with at least two short characteristic
interruptions

an N-terminal non-helical domain (head) of variable length

a non-helical C-terminal domain (tail) which shows extreme length
variation between different IF proteins

While IF proteins are evolutionary and structurally related, they have
limited sequence homologies except in several regions of the rod domain.

Lamin A is a 664 amino acid protein with a molecular weight of 70 kDa
(calculated 74,139 Da) and a pI of 7.0 (theoretical pI 7.4). Lamin A consists of a
central rod domain flanked by hydrophobic N- and C-terminal domains. After
farnesylation at the CAAX-box motif, the 18 most C-terminal amino acids of lamin-A
are removed by proteolytic cleavage to generate the mature lamin-A protein (Hennekes
& Nigg). Lamin C (572 amino
acids) differs from lamin A after amino acid 566, containing an alternative 6 amino acid
C-terminal end (VSGSRR). Lamin Adel10 has a Mw of 65 kDa and a pI
of 8 (theoretical pI 8.58). It lacks the region encoded by exon 10 , resulting
in the loss of an acidic and a polyhistidine domain.

LGMB-1B is an autosomal dominantly inherited, slowly progressive
limb girdle muscular dystrophy. LGMD-1B patients present with slowly progressive pelvic
girdle weakness with late involvement of humeral muscles and sparing of the peroneal and
tibial muscles, age-related atrioventricular cardiac conduction disturbances and dilated
cardiomyopathy. The disease was linked to chromosome 1q11-q21, with maximum LOD-scores
>6 at theta=0 (van
der Kooi et al., 1997). The region contained the LMNA-gene shown by Bonne
et al. to be mutated in the autosomal dominant form of Emery-Dreifuss muscular
dystrophy (AD-EDMD). To identify whether or not LGMD1B and AD-EDMD are allelic disorders, Muchir
et al. performed a search for mutations in the LMNA gene in patients from three LGMD1B
families linked to chromosome 1q11-q21. Mutations were identified in all affected members
of the three families: a missense mutation, a deletion of a codon and a splice donor site
mutation, respectively (Muchir).

MAD; mandibuloacral dysplasia (OMIM:
248370). Main clinical symptoms are mandibular and clavicular hypoplasia,
acroosteolysis, delayed closure of the cranial suture, joint contractures
and types A and B patterns of lipodystrophy (Simha
& Garg, 2002). Novelli
et al. (2002) identified 5 consanguineous MAD families with 9 patients,
all from a sparsely populated area from central Italy. The patients showed
no detectable muscle wasting or weakness and creatine kinase levels were
normal. Patients reported no cardiac symptoms and electrocardiograms were
normal. The lipodystrophy features of the patients made the authors test the
LMNA gene as a candidate. First, linkage analysis of the chromosome 1q21
region surrounding the LMNA gene was performed. Mulitpoint analysis
identified linkage with a maximum LOD score of 9.05 in the interval defined
by D1S2715 and D1S2721 (both were homozygous). Sequence analysis revealed a
homozygous c.1580G>A (p.Arg527His) change in exon 9 in all patients.
Heterozygous parents were healthy and showed no disease features.

HGPS; Hutchinson-Gilford progeria syndrome (OMIM:
176670) is a rare genetic disorder characterized by premature senescence, both clinically and in cell
culture. Affected children appear normal at birth, but within a year develop
characteristic features of failure to thrive, delayed dentition, alopecia and sclerodermatous skin changes.
On average, death occurs at an age of 13 years. Most patients die from progressive atherosclerosis of the coronary and
cerebrovascular arteries. Until Eriksson
et al. (2003) reported the identification of disease causing mutations
in the LMNA-gene, the prevailing hypothesis was that HGPS was a sporadic autosomal
dominant disorder. The possibility of autosomal recessive inheritance led Eriksson
et al. to perform a genome-wide scan searching for evidence of
homozygosity. No evidence of homozygosity was identified but two HGPS samples
showed uniparental isodisomy (UPD) of proximal chromosome 1q. This
ultimately led to the identification of a predominant c.1824C>T mutation
in the LMNA gene in 18/23 classical HGPS cases as well as two other
mutations in two other HGPS patients. The c.1824C>T mutation turned out
to affect splicing by creating a new splice donor site. Translation of the
resulting mRNA produces a LMNA-A protein with an internal deletion
(p.Val607_Gln656del) removing the internal proteolytic cleavage site which
is used normally to remove the last 18 C-terminal amino acids to generate
the mature LMNA protein (see also Mounkes
et al.). The authors noted several cases where a cell line contained a
secondary somatic mutation rescueing a deleterious change (twice a large
deletion and once a somatic recombination).

LDHPC; Lipoatrophy with diabetes, hepatic steatosis,
hypertrophic cardiomyopathy and leukomelanodermic papules (OMIM:
608056). In a male LDHPC patient Caux
et al. (2003) found a heterozygous change in exon 2 of the LMNA gene
resulting in an p.Arg133Leu change in the dimerization rod domain of lamins
A and C. Immunofluorescence analysis of cultured skin fibroblasts showed
nuclear disorganization and abnormal distribution of A-type lamins.

WRN; Werner's syndrome (OMIM:
277700) is a progeroid syndrome caused by mutations at the WRN helicase
locus. Chen
et al. (2003) screened 26/129 index patients with 'atypical' WRN, i.e.
having a more severe phenotype and no mutations in the RECQL2 gene, for
mutations in the LMNA-gene. Heterozygous changes in the LMNA-gene were
detected in four cases.

CCPS;Judge
et al. (ASHG meeting 2003 in Los Angeles) reported a mutation in the
LMNA gene in six patients of a four generation family with a novel dominant
disorder, designated cardiocutaneous progeria syndrome (CCPS). Clinical
manifestations involve premature aging (average age at death 36.5 years)
including graying of hair, loss of fat, wrinkled skin, dysfunction of
cardiac valves, and aggressive atherosclerosis involving the coronary,
cerebral, and peripheral arterial systems. Additional manifestations include
skin malignancy and nephrosclerosis. Genome-wide linkage analysis pointed at
a region at 1q21.2, including the LMNA-gene.

RD:Navarro
et al. (2004) reported a mutation in LMNA in two families with restrictive dermopathy (RD), also called tight skin contracture syndrome
(OMIM: 275210).
RD is a rare disorder
mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent
superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose
and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin
dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal
course. Liveborn children usually die within the first week of life.

Functionally tested variants

Mutations in the phosphoacceptor site (Ser22...)
strongly interfere with lamina disassembly (Heald
& McKeon 1990). Mutations in the two segments at either end of the ~45
kDa alpha-helical rod domain showed that these play a crucial role in in the
assembly of IF-dimers into higher order oligomers (McCormick
[1993], Stuurman
[1996]).

The Arg482Gln mutation was tested by Holt
et al. (2001) in transfected COS-cells; it did not affect the ability of
lamin A to form a nuclear lamina or to interact with the nuclear membrane
protein emerin. The consequences of changes in the lamin A/C sequence have also been studied by
Brown CA et al. (ASHG-meeting 2002, abstract 2185, Am.J.Hum.Genet. 71: S542).
Expression of an EGFP-lamin A fusion protein in mouse C2C12 or monkey COS7 cells
showed;